Abstract

Purpose: The low immunogenicity of many cancer cells and the immunosuppression by various cancers and anti-cancer therapies have been an obstacle in the development of efficacious immunotherapies. Our goal was to test if TLR agonists and anti-cancer chemotherapeutic agents synergize in rendering tumor cells more immunogenic.
Experimental design: We treated B-cell lymphoma cells with the TLR1/2 agonist Pam3CSK4 and the genotoxic anti-cancer agent Ara-C. The effects on the immunogenicity of tumor cells were measured in transfer experiments and in vitro studies.
Results: The treatment of B-cell lymphoma cells with the TLR1/2 agonist Pam3CSK4 enhanced the anti-cancer effects of the genotoxic agent Arabinofuranosyl Cytidine (Ara-C). Mice injected with co-treated tumor cells survived longer than mice challenged with Pam3CSK4 or Ara-C-treated cells. Administration of Pam3CSK4 or Ara-C reduced the tumor load of mice injected with tumor cells. Co-treatment had no effect on the rate of apoptosis or proliferation of Ara-C-treated cells, but upregulated the expression of several immunomodulatory molecules. Consistent with an increased immunogenicity of Pam3CSK4 and Ara-C-treated B-cell lymphoma cells, rejection of co-treated tumor cells depended on NK cells and T cells. We demonstrate that the upregulation of immunomodulatory molecules in response to Pam3CSK4 and Ara-C depended in part on NF-κB.
Conclusion: TLR agonists can increase the efficacy of conventional cancer therapies by altering the immunogenicity of B-cell lymphoma cells.